The interaction of CD8+ cytolytic T lymphocytes (CTL) with epithelial layers is an important but poorly defined aspect of organ allograft rejection. Recent studies demonstrating that the epithelial cell-specific integrin, CD103/beta7 (formerly alphaE integrin), defines a subset of CD8+ CTL potentially provides new insight into such interactions. The overall hypothesis to be tested in this proposal is that TGFbeta activity present at the site of rejecting allografts exerts local control over CD103 expression by a specific subset of graft infiltrating CD8+ CTL, thereby promoting the capacity of such cells for homing to, and subsequent destruction of, the graft epithelium. Mouse mixed leukocyte cultures will be utilized to elucidate the mechanisms that regulate CD103 expression by peripheral CD8 cells, and a mouse kidney transplant model will be utilized to identify the in vivo compartment in which CD103+ CTL originate during the allograft response. The stablity and extended phenotypic and functional properties of CD103+ CTL will be compared with those of conventional (CD103-) CTL, and the capacity of CD103 and CD49d to function as tissue-restricted adhesion/costimulatory molecules that promote interaction of CD103+ CTL with the graft epithelium will be defined. Transplant conditions that promote accumulation of CD103+ CTL at the graft site will also be determined; specific variables to be examined include graft cell-type, type of rejection (acute, chronic, delayed), and CsA immunosuppression. Finally, to test the central hypothesis that CD103+ CTL possess a unique capacity to infiltrate and destroy the graft epithelium, these studies will examine whether: i) the appearance of CD103+ CTL within rejecting allografts correlate with destruction of the graft epithelium, ii) depletion or blockade of CD103+ CTL inhibit destruction of the graft epithelium, and iii) adoptively transfered CD103+ CTL home to the renal epithelium and elicit destructive lesions characteristic of rejection pathology. Together, these studies will fulfill a form of Koch's postulates to demonstrate that CD103+ CTL are an important mechanism of graft destruction. Human MLC cultures and clinical renal transplant specimens will be utilized to confirm relevance to the human system. These studies will provide new insight into the immunologic basis of renal allograft rejection, and have the potential to identify novel targets for therapeutic intervention in rejection events.